Recent studies from this laboratory have resulted in the delineation of metal ions as the regulators of cellular heme and drug metabolism and have made it possible to define a major dimension of metal toxicity in terms of a unified cellular mechanism of action. These studies have brought to focus the role of microsomal heme oxygenase as an enzyme of major importance for the catabolism of microsomal cytochromes. Accordingly, the objectives of the proposed studies are to further our present knowledge of the role of toxic metal ions in the regulation of the cellular heme and drug metabolism and to expand the range of our studies to include several additional facets of this problem. These studies would include (1) the investigation of the role of metal ions and heme degradation activity on the depressed capacity of newborn to synthesize hemoproteins and carry out drug metabolism activities; (2) the further characterization of the enzymes of heme metabolism pathway; (3) the investigation of the effects of repeated exposure to metal ions on the response of cellular heme metabolism and detoxification system to a secondary chemical; and (4) to elucidate the cellular basis of the enhanced rate of degradation of the hemoprotein in response to metal ions.